This proposal "tyrosine kinases and prostate cancer" began in 1998 with the development of tyrosine kinase display approach and the first comprehensive tyrosine kinase profile of prostate cancer cells. In the ensuing years, tyrosine kinases involved in neuroendocrine differentiation and androgen independence were identified and the processes characterized. This led to the discovery of a complex of tyrosine kinases Src, Etk and FAK (referred to as Src kinase complex) as a central integrator of signals emanating from tyrosine kinase receptor, cytokine receptor and G-protein coupled receptor. These tyrosine kinases present novel targets for potential therapeutic intervention. The present proposal is focused on prostate cancer biology and etiology, especially the involvement of Src/Etk tyrosine kinase complex in prostate carcinogenesis and androgen independence conversion. The potential of Src and Etk to serve as therapeutic targets will be explored. Our results in the past grant period contributed to the basic understanding of the roles of neuroendocrine differentiation and neuropeptide in androgen independent growth of prostate cancers, the involvement of Src kinase complex in inappropriate activation of androgen receptor, and the oncogenic role of Etk tyrosine kinase in prostate carcinogenesis. In addition, with our collaborators, we developed in vivo prostate cancer mouse models and potential inhibitors for the Src/Etk complex. Yet, the detailed mechanisms whereby Src kinase complex activates androgen receptor and the inhibitors of Src kinase complex induce cell killing remain largely unknown. Taking advantage of the discoveries and the reagents developed in the past grant period, the present proposal is designed to provide a better understanding of the mechanisms whereby Src tyrosine kinase complex activates androgen receptor and protects prostate cancer cells from autophagic and apoptotic death. PUBLIC HEALTH RELEVANCE: One of the most troubling aspects of prostate cancer is its evolution to androgen independence, to which no effective treatment has been developed. The present proposal deals directly with the mechanisms of this evolution and has identified several key tyrosine kinases involved in this process. In addition, this proposal will provide important information concerning the mechanisms of cell killing by tyrosine kinase inhibitors and test the potential benefits of using these inhibitors in treating prostate cancers.